1. Field of the Invention
The present invention relates to an emulsion composition for the intravenous administration of pharmacologically active agents, as well as methods for preparation thereof.
2. Description of the Related Art
Docetaxel is an antineoplastic agent belonging to the taxoid family. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α-,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate. Docetaxel has the following structural formula:

Docetaxel is highly lipophilic and practically insoluble in water. Because of the ester group (N-tert-butyl ester), docetaxel is very unstable in the presence of water as hydrolysis of the N-tert-butyl ester can take place rapidly.
In order to inject docetaxel intravenously, the marketed product (TAXOTERE™) is provided as a yellow viscous liquid containing docetaxel dissolved in almost 100% polysorbate 80, which is used as solubilizer for docetaxel. Polysorbate 80, like other detergents, is, however, very toxic. Upon intravenous injection, it causes severe allergic or hypersensitivity reactions that can be fatal. For this reason, the FDA has requested the drug maker to place a the following strong warning (“black box” warning) on the TAXOTERE™ label:
“Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received the recommended 3-day dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the TAXOTERE infusion and administration of appropriate therapy. TAXOTERE must not be given to patients who have a history of severe hypersensitivity reactions to TAXOTERE or to other drugs formulated with polysorbate 80.”
Many efforts have been made to provide safer formulations for insoluble intravenous (IV) drugs such as docetaxel. The best-known example is another insoluble taxoid analog drug paclitaxel, which in its marketed product (TAXOL®) utilizes another immunogenic detergent called cremophor. Some improvements in solubilization methods have been reported for paclitaxel. These new formulations of paclitaxel represent improvements over the TAXOL® formulation. However, when it comes to the docetaxel formulation, virtually all previously reported solubilization methods for paclitaxel or docetaxel appear to suffer one or more of the following drawbacks:
(1) They contain toxic, allergenic or vein irritating excipients including solvents (e.g., ethanol, DMA, DMSO, propylene glycol, and n-methylpyrrolidon), solubilizers (e.g., polysorbates, cremophor, and bile salts), materials derived from an animal source with risk of virus contamination (e.g., human albumin) or chemicals that have no proven record of safe use (e.g., vitamin E TPGS).
(2) They contain water. As indicated above, docetaxel is incompatible with water.
(3) They are unstable and unable to deliver the required dose of docetaxel without a large and pharmaceutically unsafe amount of excipients such as phospholipids (as in liposome) or oil (previously known emulsions).
Accordingly, there is a need for developing a safe and stable formulation to deliver docetaxel and other water insoluble drugs. The present invention meets this need and provides additional related advantages.